Millions of people suffer from chronic or intractable pain. Persistent pain varies in etiology and presentation. In some cases, symptoms and signs may be evident within a few weeks to a few months after the occurrence of an injury or the onset of disease, e.g. cancer or AIDS. Like many illnesses that at one time were not well understood, pain and its many manifestations may be poorly treated and seriously underestimated. Inappropriately treated pain seriously compromises the patient""s quality of life, causing emotional suffering and increasing the risk of lost livelihood and disrupted social integration. Severe chronic pain affects both the pediatric and adult population, and often leads to mood disorders, including depression and, in rare cases, suicide.
In the last several years, health policy-makers, health professionals, regulators, and the public have become increasingly interested in the provision of better pain therapies. This interest is evidenced, in part, by the U.S. Department of Health and Human Services"" dissemination of Clinical Practice Guidelines for the management of acute pain and cancer pain. These publications state that opioids are an essential part of a pain management plan. There is currently no nationally accepted consensus for the treatment of chronic pain not due to cancer, yet the economic and social costs of chronic pain are substantial, with estimates ranging in the tens of billions of dollars annually.
Opioids are the major class of analgesics used in the management of moderate to severe pain because of their effectiveness, ease of titration, and favorable risk-to-benefit ratio. Opioids produce analgesia by binding to specific receptors both within and outside the CNS. Opioid analgesics are classified as full agonists, partial agonists, or mixed agonist-antagonists, depending on the specific receptors to which they bind and their intrinsic activity at that receptor.
Three subclasses of opioid receptor have been identified in humans, namely the xcex4-, xcexa-, and xcexc-opioid receptors. Analgesia is thought to involve activation of both xcexc and xcexa receptors. Notwithstanding their low selectivity for xcexc over xcexa receptors, it is likely that morphine and morphine-like opioid agonists produce analgesia primarily through interaction with xcexc receptors; selective agonists of xcexa receptors in humans produce analgesia, but rather than the euphoria associated with morphine and congeners, these compounds produce dysphoria and psychotomimetic effects. The consequences of activating xcex4 receptors in humans remain unclear.
Commonly used full agonists include morphine, hydromorphone, meperidine, methadone, levorphanol, and fentanyl. These opioids are classified as full agonists because there is not a ceiling to their analgesic efficacy, nor will they reverse or antagonize the effects of other opioids within this class when given simultaneously. Side effects include constipation, nausea, urinary retention, confusion, sedation, and respiratory depression. Morphine is the most commonly used opioid for moderate to severe pain because of its availability in a wide variety of dosage forms, its well-characterized pharmacokinetics and pharmacodynamics, and its relatively low cost. Meperidine may be useful for brief courses (e.g., a few days) to treat acute pain and to manage rigors (shivering) induced by medication, but it generally should be avoided in patients with cancer because of its short duration of action (2.5 to 3.5 hours) and its toxic metabolite, normeperidine. This metabolite accumulates, particularly when renal function is impaired, and causes CNS stimulation, which may lead to dysphoria, agitation, and seizures; meperidine, therefore, should not be used if continued opioid use is anticipated.
Buprenorphine is an example of a partial agonist. Buprenorphine has a relatively low intrinsic efficacy at the opioid receptor in comparison to full opioid agonists, and it displays a ceiling effect to analgesia. Clinical studies found buprenorphine to be effective in the treatment of heroin addiction and to have some advantages over methadone in terms of relative safety. Buprenorphine also reduces cocaine abuse in individuals who are dependent on both heroin and cocaine. The dual effects of buprenorphine provide new insight into the mechanisms of cocaine and heroin dependence; these observations suggest, furthermore, that the underlying mechanisms of these dependencies may be similar.
Mixed agonist-antagonists in clinical use include pentazocine, butorphanol tartrate, and nalbuphine hydrochloride. These drugs have an analgesic ceiling. In contrast to full agonists, these drugs block opioid analgesia at one type of opioid receptor (xcexc) or are neutral at the xcexc receptor while simultaneously activating a different opioid receptor (xcexa). Patients receiving full opioid agonists should not be given a mixed agonist-antagonist because doing so may precipitate a withdrawal syndrome and increase pain.
The development of physical dependence with repeated use is a characteristic feature of the opioid drugs, and the possibility of developing drug dependence is one of the major limitations of their clinical use. Almost all opioid users rapidly develop drug dependency which can lead to apathy, weight loss, loss of sex drive, anxiety, insomnia, and drug cravings.
Historically, the development of analgesic tolerance was believed to limit the ability to use opioids efficaciously on a long-term basis for pain management. Tolerance, or decreasing pain relief with the same dosage over time, has not proven to be a prevalent limitation to long-term opioid use. Experience with treating cancer pain has shown that what initially appears to be tolerance is usually progression of the disease. Furthermore, for most opioids, there does not appear to be an arbitrary upper dosage limit, as was once thought.
Cessation of opioid administration may result in withdrawal. Symptoms of withdrawal are often the opposite of the effects achieved by the drug; withdrawal from morphine, however, results in complex symptoms that may seem unrelated to its effects. Misunderstanding of addiction and mislabeling of patients as addicts result in unnecessary withholding of opioid medications. Addiction is a compulsive disorder in which an individual becomes preoccupied with obtaining and using a substance, the continued use of which results in a decreased quality of life. Studies indicate that the de novo development of addiction is low when opioids are used for the relief of pain. Furthermore, even opioid addicts can benefit from the carefully supervised, judicious use of opioids for the treatment of pain due to cancer, surgery, or recurrent painful illnesses such as sickle cell disease.
Zadina et al. recently reported the isolation and characterization of endomorphins 1 (1) and 2 (2) (Nature 1997, 386, 499-502). The endomorphins are tetrapeptides, isolated from bovine frontal cortex, that selectively bind in vitro to the xcexc-opioid receptor; 1 (Seq. ID No.1) and 2 (Seq. ID No.2) select for xcexc over xcex4 receptors by factors of 4,183 and 13,381, respectively; and 1 (Seq. ID No.1) and 2 (Seq. ID No.2) select for xcexc over xcexa receptors by factors of 15,077 and 7,594, respectively. Additionally, 1 (Seq. ID No.1) and 2 (Seq. I.D. No.2) are potent analgesics in vivo; intracerebroventricular injections to mice of 1 (Seq. ID No.1) and 2 (Seq. ID No.2) established ED50 values of 8.4 xcexcg and 2.9 xcexcg, respectively. Finally, the analgesic effects of the endomorphins were antagonized by naloxone and xcex2-funaltrexamine. 
Oligopeptides do not easily cross the GI/blood and blood/brain barriers. This problem cannot be attributed solely to a lack of metabolic stability. Crossing both the GI/blood and blood/brain barriers are key steps when considering using a peptide as a drug. While several peptides have been successfully stabilized against degradation, their bioavailability, namely their ability to cross the blood/brain barrier remained problematic.
In particular, neuropeptides, e.g. the endomorphins, undergo fast proteolytic degradation in the gastrointestinal tract, in blood and in other tissues. The pharmacokinetics of neuropeptides in the synapse are distinct from those of a peptide elsewhere. In the synapse, the time required for the neuropeptides to accomplish their function is very short in part due to the short distances involved. The endogenous proteases which are responsible for terminating the activity of a given neuropeptide are the only ones present in the vicinity, and they degrade the peptide immediately after completion of its function. In order to devise a therapeutic peptide for this setting, its structure should be stabilized against the synaptic proteases responsible for its degradation, as well as against other proteases present in the GI tract, blood and other tissues.
Moreover, biologically active oligopeptides exist in solution as a mixture of rapidly interconverting conformers (Kessler, H., Angew. Chem., Int. Ed. Eng., 21, 512 (1982); this fact may lead to a lack of receptor selectivity and unanticipated susceptibility to proteolysis (Veber, D. F. and Freidinger, R. M., Trends in Neurosci. 8, 392 (1985). Furthermore, the numerous conformational equilibria can obscure the identities of the biologically active conformers of the oligopeptide. Structural modifications of an oligopeptide that reduce the conformational space available to it have the potential to mitigate side-effects, and/or its degradation, by eliminating the conformations responsible for the side-effects, and/or those required by the degradation enzymes, respectively. These characteristics of naturally occurring peptides, e.g. neuropeptides, are of great significance and constitute major challenges in applying the peptide as a drug, as well as understanding the pharmacological and molecular interaction between the peptide and its receptor. For example, analgesic peptidomimetic opiates, which are xe2x80x9cimitationsxe2x80x9d of endogenous enkephalins, were developed through research which was more random than rational and did not take into consideration all the factors described above.
In many cases, the peptidomimetics that result from a peptide structural lead using the xe2x80x9crationalxe2x80x9d approach comprise unnatural xcex1-amino acids. Recently, fundamental research on the use of norpeptidic scaffolds, such as steroidal or sugar structures, to anchor specific receptor-binding groups in fixed geometric relationships have been described (see for example Hirschmann, R. et al., 1992 J. Am. Chem. Soc., 114:9699-9701; and Hirschmann, R. et al., 1992 J. Am. Chem. Soc., 114:9217-9218).
There exists a need to provide alternative and improved agents for the treatment of pain, particularly for the treatment of chronic pain, e.g. pain associated with cancer and AIDS. Opioids, specifically ligands for the xcexc-opioid receptor, are the major class of analgesics used in the management of moderate to severe pain because of their effectiveness, ease of titration, and favorable risk-to-benefit ratio. Unfortunately, the opioids currently available are addictive to varying degrees. Research into the development of new, selective ligands for opioid receptors holds the promise of yielding potent analgesics that lack the addictive characteristics of morphine and its congeners.
The present invention is directed to the use of organic moleculesxe2x80x94e.g. tetrapeptides, derivatives and analogs thereof, and the respective pharmaceutical formulations thereofxe2x80x94in the treatment of chronic pain. Specifically proposed as analgesic agents are compounds, and pharmaceutical formulations thereof, based on endomorphin 1 (1) (Tyr-Pro-Trp-Phe-NH2)(Seq. ID No.1), endomorphin 2 (2) (Tyr-Pro-Phe-Phe-NH2)(Seq. ID No.2), and analogs and derivatives thereof (for the disclosure of the endomorphins, see: Zadina et al. Nature 1997, 386, 499-502). The wide range of novel analgesic compounds disclosed herein enables the potential to tailor potency, specificity, solubility, bioavailability, stability, toxicity, and other physical properties to suit specific purposes.